The present invention relates to novel substituted tetrahydropyridine and piperidinecarboxylic acids and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are muscarinic antagonists.
The physiological actions of the neurotransmitter acetylcholine are mediated by two types of receptors, generally known by the terms `nicotinic` and `muscarinic`. Of particular interest are muscarinic cholinergic receptors, which mediate the effects of acetylcholine in the central as well as the peripheral nervous systems (CNS and PNS, respectively) [Taylor P., Brown J. H. in Basic Neurochemistry, 4th Edition; Siegel G., Agranoff B., Albers R. W., Molinoff P., Eds., Raven Press, New York: 1989:203-231]. Muscarinic receptors also play an important role in mediating the actions of acetylcholine on certain organs that are particularly responsive to cholinergic stimulation; for example, they affect the contractibility of smooth muscle in the gastrointestinal tract [Grider J. R., Bitar K. N., Makhlouf G. M., Gastroenterology 1987;93:951-957], the secretion of gastric acid [Kromer W., Gonne S., Int. J. Exp. Clin. Pharmacol. 1988;37(Suppl. 1):48-53], the force and rate of heart muscle contraction [Melchiorre C., Cassinelli A., et al., Trends Pharm. Sci. 1988;(Supplement):55], the secretory activity of exocrine glands that receive parasympathetic innervation, such as the salivary glands [Goyal R., N. Engl. J. Med. 1989;321:1022-1029], and the constriction of bronchial tissue [Maclagan J., Barnes P., Trends Pharmacol. Sci. 1989; (Suppl. "Subtypes of Muscarinic Receptors IV"):88-92], among others.
The existence of multiple muscarinic cholinergic receptor subtypes has been documented by functional, binding, and molecular biology studies. Initially, 3 muscarinic receptor subtypes (M.sub.1, M.sub.2, M.sub.3) were characterized pharmacologically by the ability of certain synthetic ligands to recognize each receptor subtype with relative selectivity [Doods H. N., et al., J. Pharmacol. Exp. Ther. 1987;242:257-262; Levine R. R., Birdsall N. J. M., et al., Trends Pharmacol. Sci. 1989; (Suppl. "Subtypes of Muscarinic Receptors IV"):vii]. M.sub.1 Receptors, found in the CNS and peripheral ganglia, are recognized with high affinity by the muscarinic antagonist pirenzepine. M.sub.2 receptors, located primarily on cardiac cells, display high affinity towards the antagonists methoctramine and AF-DX 116; and M.sub.3 receptors, found in smooth muscle and exocrine glands, are recognized with high affinity by the antagonists 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methobromide) and hexahydrosiladifenidol.
At the molecular level, genes encoding 5 distinct muscarinic receptors have been cloned. The encoded receptor proteins have been termed m1, m2, m3, m4, and m5 [Bonner T. I., Trends Pharmacol. Sci. 1989; (Suppl. "Subtypes of Muscarinic Receptors IV"):11-15; Bonner T. I., Buckley N. J., Young A. E., Brann M. R., Science 1987;237:527-532; Hulme E. C., Birdsall N. J. M., Buckley N. J., Ann. Rev. Pharmacol. Toxicol. 1990;30:633-673]. These receptors possess different amino acid sequences and are selectively expressed throughout the body and in specific brain regions. mRNA for the m1 receptor has been found in the brain and exocrine glands; m2 mRNA is found in the heart, smooth muscle, and brain; m3 mRNA is detected in brain, glands, and smooth muscle; m4 and m5 mRNA are found primarily in the brain [Bonner T. I.; T.I.N.S. 1989;12:148-151]. The pharmacologically defined M.sub.1, M.sub.2, and M.sub.3 receptors correspond quite closely to the molecularly defined m1, m2, and m3 receptors.
As indicated above, muscarinic receptors mediate the parasympathetic branch of the autonomic nervous system, which primarily controls gastric and intestinal tone and motility, gastric acid secretion, salivation, urination, lacrimation, cardiac, and ocular functions. Current and potential therapeutic applications of muscarinic antagonists include the treatment of peptic ulcers, irritable bowel syndrome, chronic obstructive airways disease, gastrointestinal, biliary, and urinary tract spasms, ophthalmic applications (as mydriatics and cycloplegics), reduction of excessive salivary or bronchial secretions during inhalation anesthesia, and the symptomatic treatment of parkinsonian movement disorders. The main limitations associated with the clinical use of available muscarinic antagonists stem from their relative lack of selectivity for the various muscarinic receptor subtypes. Thus, most muscarinic antagonists will produce many of the following side-effects in humans: cognitive impairment via blockade of brain muscarinic receptors, mydriasis, dry mouth, tachycardia, decreased sweating, blurred vision (by relaxation of the ciliary muscle), decreased gastrointestinal motility and constipation, etc. The lack of selectivity among these effects makes it difficult to address therapy in one specific indication.
Since individual therapeutic effects are associated with blockade of one or more specific muscarinic receptor subtypes, selective muscarinic antagonists with high specificity for the desired receptor subtypes would be very useful. These agents should provide the desired therapeutic benefit without the many unwanted side-effects of nonselective muscarinic antagonists. Currently available muscarinic antagonists can be classified into 3 main groups, based on their receptor subtype selectivity [Doods H. N., Drug News Perspect. 1992;5:345-352]: (1) agents such as pirenzepine, with the following type of receptor subtype selectivity: m1&gt;m4&gt;m3, m5, m2; (2) agents such as the cardiac-selective antagonist AF-DX 116: m2&gt;m4, m1&gt;m3, m5; and (3) what could be classified as non-m2 antagonists, exemplified by UH-AH 37: m1, m3, m4, m5&gt;m2.
The following are just a few of the potential therapeutic uses of muscarinic antagonists with specific receptor subtype selectivities. Of course, nonselective antagonists might also be useful for these indications, but the side effects described above will limit their useful dosing range. In general, the molecular biology classification for the muscarinic receptor subtypes (m1, m2, m3, m4, m5) will be used, even though some of the agents' specificities may have been defined pharmacologically in the literature (M.sub.1, M.sub.2, M3).
Inhibition of Gastric Acid Release
Blockade of muscarinic receptors inhibits basal and stimulated gastric acid secretion, mainly by reducing volume secretion, an effect that is presumably mediated by m1 receptors. It has been clearly demonstrated that m1 antagonists possess utility in the treatment of peptic lesions, such as reflux esophagitis and gastric and duodenal ulcers [Stockbrugger R. W., Meth. Find. Exp. Clin. Pharmacol. 1989;11(Suppl. 1):79-86]. The effects of the relatively m1-selective antagonist pirenzepine, for example, have been extensively documented [Carmine A. A., Brogden R. N., Drugs 1985;30:85-126; Kromer W., Gonne S., Int. J. Exp. Clin. Pharmacol. 1988;37(Suppl. 1):48-53].
Antibradycardic Agents
Selective m2 muscarinic antagonists may be useful in the treatment of certain cardiovascular conditions, such as sinus bradycardia and bradycardic-hypotension syndrome after myocardial infarction. One of the best-known agents of this type is AF-DX 116, which is currently undergoing clinical evaluation as an antibradycardic drug [Doods H. N., Engel W., Su CAPF, Tanswell P., Cardiovasc. Drug Rev. 1991;9:30-40].
In a related application, m1 antagonists, such as pirenzepine, have been shown to improve exercise tolerance in patients with effort myocardial ischemia [Marraccini P., Orsini E., et al., Am. J. Cardiol. 1992;69:1407-1411].
Bronchodilators
Selective m1 antagonists may be useful in the treatment of those forms of asthma in which reflex mechanisms and/or increased cholinergic tone play a role, e.g., nocturnal asthma [Doods H. N., Drug News Perspect. 1992;5:345-352]. Mixed m1/m3 antagonists (e.g., DS-AH 14) have shown promise in the treatment of obstructive airway disease [Doods H. N., Drug News Perspect. 1992;5:345-352]. Also useful are muscarinic antagonists with the subtype selectivity profile m1&gt;m3&gt;m2, such as DAC 5889 [Doods H. N., Drug News Perspect. 1992;5:345-352]. Selective m3 antagonists have also been found to possess potential for the treatment of airway disease [Maclagan J., Barnes P., Trends Pharm. Sci. 1989; (Suppl. "Subtypes of Muscarinic Receptors IV"):88-92; Minette P. A., Barnes P. J., Am. Rev. Respir. Dis. 1990;141:S162-S165]. The muscarinic antagonist ipratropium bromide is used clinically as an inhalation bronchodilator.
In a related application, it is known that the parasympathetic nervous system regulates glandular secretion in the upper and lower respiratory tracts [Ishii T., Pract. Otorhinolaryngol. 1970;32:153-158]. Muscarinic m1 and m3 receptor subtypes regulate mucous secretion from human nasal mucosa, but m3 receptors may possess the predominant effects [Mullol J., Baraniuk J. N., et al., J. Appl. Physiol. 1992;73:2069-2073]. Mixed m1/m3 antagonists may be useful in allergic rhinitis, bronchial asthma, chronic bronchitis, etc.
Urinary Incontinence
Urinary incontinence can be the result of an overactive or unstable detrusor muscle. Muscarinic antagonists, exemplified by the agent oxybutynin, may play a role in the therapeutic treatment of the condition [Tonini M., et al., J. Pharm. Pharmacol. 1987;39:103-107]. Main limitations in the use of this agent include mydriasis, dry mouth, and some of the other typical anticholinergic side effects mentioned above. Muscarinic antagonists with some selectivity for m2 and/or m3 receptors have been suggested as potentially advantageous in the treatment of urinary incontinence [Kaiser C., Audia V. H., et al., J. Med. Chem. 1993;36:610-616].
CNS Uses of Muscarinic Antagonists
In the central nervous system (CNS), cholinergic neurotransmission is mediated primarily by muscarinic receptors. In hippocampus and regions of the cerebral cortex, they seem to be critical for higher cognitive processes such as memory and learning. In the striatum and motor cortex, they are involved in the control of movement. The collection of movement disorders typical of Parkinson's disease (tremor, rigidity, bradykinesis, etc.) results from a neurotransmitter imbalance in the basal ganglia, namely the loss of the inhibitory nigrostriatal dopaminergic circuitry which results in an excess of striatal acetylcholine. As a result, muscarinic antagonists are widely used in the early stages of Parkinson's disease [Fahn S., Caine D. B., Neurology 1978;28:5-7]. Muscarinic antagonists are also useful for the treatment of dystonias (e.g., torticollis) [Fahn S., Neurology 1983;33:1255-1261] and the parkinsonian movement disorders frequently associated with dopamine antagonist drug therapy (e.g., antiemetics and antipsychotics).
Alzheimer's disease is characterized by the progressive degeneration of cholinergic neurons that project from the basal forebrain to the cerebral cortex and hippocampus [Coyle J. T., Price D. L., DeLong M. R., Science 1983;219:1184-1190]. Cholinomimetic therapy (direct or indirect enhancement of the effects of endogenous acetylcholine) is currently viewed as the most promising short-term symptomatic treatment for the disease. Blockade of muscarinic m2 autoreceptors (located on cholinergic nerve terminals) is thought to stimulate the release of acetylcholine from cholinergic neurons [Raiteri M., Leardi R., Marchi M., J. Pharmac. Exp. Ther. 1984;228:209-214; Mash D. C., Potter L. T., Neuroscience 1986;19:551-564]. Thus, selective m2 antagonists might be useful as acetylcholine-releasing agents for the treatment of Alzheimer's disease and other dementias associated with cholinergic insufficiency.
Antispasmodics
Additionally, selective m3 muscarinic antagonists are useful as antispasmodics (treatment of atonic conditions of the gut and bladder [Mutschler E., Feifel R., et al., Eur. J. Pharmacol. 1990;183:117-119]. As such, they may find utility in conditions such as irritable bowel syndrome (IBS).
METHODOLOGY FOR THE DETERMINATION OF MUSCARINIC RECEPTOR SUBTYPE SELECTIVITY
As indicated above, conventional pharmacological classification of muscarinic receptor subtypes was based on the relative selectivity of certain muscarinic antagonists for the M.sub.1, M.sub.2, and M.sub.3 receptors. Tissue preparations are frequently used for this type of work. However, the results are often clouded by the fact that most tissues express more than one muscarinic receptor subtype. Recently, each subtype of human muscarinic receptor has been stably cloned and expressed in Chinese hamster ovary (CHO) cells. These cell lines have been used to determine the relative affinity of novel muscarinic antagonists for each of the 5 cloned human muscarinic receptor subtypes [Buckley N. J., Bonner J. I., Buckley C. M., Brann M. R., Mol. Pharmacol. 1989;35:469-476; Dorje F., Wess J., et al., J. Pharm. Exp. Ther. 1991;256:727-733]. An additional advantage of these cloned cell lines is the ability to perform measures of functional activity directly on these cell cultures. Preferentially coupled to the stimulation of phosphoinositide metabolism via phospholipase C activation are m1, m3, and m5 receptors, while m2 and m4 receptors are coupled to the inhibition of adenylate cyclase [Peralta E. G., Ashkenazi A., et al., Nature 1988;334:434-437]. This knowledge allows the classification of compounds that bind to a specific receptor subtype as receptor agonists or antagonists. PG,10 Using this technology, novel subtype-selective muscarinic antagonists have now been discovered and are the subject of this invention.
U.S. Pat. No. 4,745,123 ("'123") discloses a series of substituted 1,2,3,6-tetrahydro- and 1,2,5,6-tetrahydropyridine-3-carboxylic acids, esters, and amides possessing muscarinic binding activity and which are useful for the treatment of the symptoms of senile cognitive decline. However, unlike the compounds disclosed in the '123 patent, the compounds of the present invention are muscarinic antagonists and also possess marked selectivity for m1 and m4 muscarinic receptors over m2, m3, and m5, making them ideal agents in situations where selective blockade of m1 and/or m4 receptors is desired, e.g., gastric ulcers and Parkinson's disease, respectively.